Paroxysmal nocturnal hemoglobinuria

Background

• Intravascular hemolysis caused by increased sensitivity of RBCs to hemolytic action of complement

Pathophysiology

• Abnormal PIG-A gene > defect in GPI-linked anchor > partial/complete absence of GPI-linked proteins (mainly CD55 and CD59) > increased sensitivity of RBCs to hemolytic action of complement
• Hemolysis precipitated by stresses that activate complement (eg infection)
  • Nocturnal hemolysis attributed to intestinal absorption of lipopolysaccharide (strong activator of complement) at night

Clinical Features

• Abdominal pain or back pain
• Intravascular hemolysis
• Renal failure (both from intravascular hemolysis causing AKI and chronic hemolysis causing iron deposition in kidneys)
• DVT, thrombosis of hepatic/intraabdominal/cerebral veins, arterial thrombosis
• Bone marrow failure leading to aplastic anemia
• Myelodysplastic syndrome (MDS) or myeloproliferative disorders
• Acute leukemia
• Esophageal spasm
• Crampy abdominal pain
• Impotence/ED
• May progress to aplastic anemia

Differential Diagnosis

Microangiopathic Hemolytic Anemia (MAHA)

• Disseminated Intravascular Coagulation (DIC)
• Thrombotic Thrombocytopenic Purpura (TTP)
• Hemolytic Uremic Syndrome (HUS)
• HELLP syndrome
• Heparin-Induced Thrombocytopenia (HIT)
• Hereditary spherocytosis
• Paroxysmal nocturnal hemoglobinuria
• Malignant hypertension
• Antiphospholipid syndrome
• Scleroderma
• Antiphospholipid Syndrome (APS)
• Paroxysmal Nocturnal Hemoglobinuria (PNH)
• Other medical causes: malignancy, renal allograft rejection, vasculitides like polyarteritis nodosa and Wegener's granulomatosis
• Drugs: chemotherapy; Clopidogrel (Plavix) associated with TTP
• Nonvascular causes: prosthetic valve (more common with mechanical, more common at aortic valve), LVAD, TIPS, coil embolization, patched AV shunt, AVM

Evaluation

• Anemia
• Negative Coombs test
• Hemoglobinuria
• Elevated LDH
• Decreased haptoglobin
• Positive sucrose lysis test or Ham test (both test sensitivity of RBCs to lysis by complement). Ham's test is when the patient's cells are incubated in acidified serum, which triggers the alternative compliment pathway, resulting in lysis of PNH cells. Sucrose lysis test is when the patient's serum is mixed in sucrose, which causes hemolysis of PNH cells.
• Other clues: granulocytopenia/thrombocytopenia, venous thrombosis, aplastic anemia, MDS, dysphagia or abdominal pain
• Flow cytometry of cell membrane proteins (CD55 and CD59) is a sensitive test for PNH

Management

• Eculizumab (C5 antibody): stops hemolysis in PNH
• Iron/folate supplements
• RBC transfusion PRN
• Prednisone may decrease RBC destruction
• For severe hematopoietic dysfunction with marked cytopenias: hematopoietic cell transplant or immunosuppression (cyclosporine or antithymocyte globulin)
• Anticoagulation for thrombosis

See Also

Authors

Matthew Hankerson, Anthony Lucero, Ross Donaldson, Claire, Neil Young